The present invention relates to the prevention, treatment and amelioration of neurodegenerative or Alzheimer's disease, and more particularly to the prevention, treatment and amelioration of Alzheimer's disease with new heterocyclic compounds which act as inhibitors of central cholinesterase enzyme following the indirect cholinomimetic pathway described in the following bibliographic references:    1)—Kasa P, Rakonczay Z, Gulya K. The cholinergic system in Alzheimer's disease. Prog Neurobiol. 1997 August; 52(6):511-35.    2)—Francis P T, Palmer A M, Snape M, Wilcock G K. The cholinergic hypothesis of Alzheimer's disease: a review of progress.    3)—Davies P, Maloney A J F. Selective loss of central cholinergic neurones in Alzheimer's Disease. Lancet. 1976; ii: 1403.    4)—Bartus R. T., Dean R. L., Beer B and Lippa A. S. The cholinergic hypothesis of geriatric memory dysfunction. Science 1982; 217: 408-17.    5)—Taylor P. Development of acetylcholinesterase inhibitors in the therapy of Alzheimer's Disease. Neurology 1998; 51(1): S30-S35
Alzheimer's disease (AD) is characterised by a progressive, inexorable loss of cognitive function associated with an excessive number of senile plaques in the cerebral cortex and subcortical gray matter, which also contains amyloid and neurofibrillary tangles consisting of tau protein. While early-onset forms of AD account for 2%-7% of cases, the common form affects persons greater than 60 years old, and its incidence increases as age advances. Million of humans have AD, and the annual cost of the disease is very high.
Some pyridinium or quinolinium carbamate derivatives have been disclosed as acetylcholineserase inhibitors in WO97/08146; in Wuest & al JACS vol 73, 1951 p. 1210-1216; in Wang & al nuclear medicine and biology vol 31, no. 7 October. 2004, p. 957-964; in Mishra & al ACS symposium series vol 806, 2002, p. 289-306; in Radio & al Biochemistry, vol 31, 1992, p. 9760-9767; in Badwi & al Oriental J. of Chemistry, vol 4, no. 1, 1988, p. 76-83; and in Kitz & al Biochemical Pharmacology vol 16, 1967, p. 2201-2209. Nevertheless these compounds present the drawback of being unstable in vivo and very rapidly desactivated.
Today, only few cholinesterase inhibitors agents are known and used as a drug for the treatment of AD. These agents are Donepezil (1), Galantamine (2) and Rivastigmine (3). However the major drawback with these molecules is the loss of their therapeutical effect with time.
Thus the need of increasing the daily doses increases the side effects, until the interruption of the treatment. It is known that these side effects are specifically caused by the peripheral activity of these molecules on cholinesterase enzyme.
There is a need for new cholinesterase inhibitors agent which could act against neurodegenerative diseases. There is a need for anti Alzheimer molecules which decrease or avoid the side effects of the known commercial drugs. Specifically there is a need for new compounds which could act as anti-Alzheimer agents without interacting with peripheral cholinesterase enzyme.